If intracellular [Ca++] is still elevated, myosin undergoes another cross-bridge cycle and produces further contraction of the muscle. The ratchet action of the cross-bridge is capable of moving the thin filament approximately 10 nm. The cycle continues until the SERCA pumps Ca++ back into the SR. As [Ca++] falls, Ca++ dissociates from troponin C, and the troponin-tropomyosin complex moves and blocks the myosin binding sites on the actin filament. If the supply of ATP is exhausted, as occurs with death, the cycle stops abnormalityisseeninmusclesofthelegs,arms,andeyelid,andtheresponseisworsenedincoldweather.Brody’sdiseasecanbeeitherautosomalrecessiveorautosomaldominantandmayinvolvemutationsinuptothreegenes;however,itisrare(affecting1per10,000,000births).ItappearstoresultfromdecreasedactivityoftheSERCA1Ca++ pumpfoundinfast-twitchskeletalmuscle(seethesection ”).ThedecreasedactivityofSERCA1hasbeenassociatedwithmutationsinthegenethatencodesSERCA1,althoughanotheraccessoryfactormaycontributetothedecreasedSRCa++ uptakeinthefast-twitchskeletalmuscleofindividualswithBrody’sdisease.
Myotoniacongenitaisalsoassociatedwithprolongedmusclecontractions(painlesscramping)aftervoluntarycontractions,asaresultofmutationsintheCLCN1 gene,whichencodesthechloridevoltage-gatedchannel1inskeletalmusclesarcolemmaandTtubules.Chlorideconductanceintheskeletalmuscleisimportantforrepolarizationandstabilizationofthemembranepotential,andsothereducedchlorideconductanceinskeletalmusclesofindividualswithmyotoniacongenitaresultsinhyperexcitabilityofthemusclefiber.Voluntarycontractionmaythereforebefollowedbyaseriesofactionpotentials(afterdepolarizations)inthemusclethatresultinprolongedcontractions(i.e.,cramping).Epinephrine(e.g.,duringstressfulsituations)oftenworsensthecondition,asshowninmyotonic(“fainting”)goats.Musclestiffnesscanberelievedbyrepeatedcontractions(i.e.,thewarm-upphenomenon),althoughthemechanismunderlyingthewarm-upphenomenonisnotknown.MutationsintheCLCN1 geneinmyotoniacongenitamaybetransmittedineitheranautosomalrecessivemanner(asinBecker’sdisease,onetypeofmyotoniacongenita)oranautosomaldominantmanner(asinThomsen’sdisease,theothertypeofmyotoniacongenita).Theprevalenceofmyotoniacongenitaisapproximately1per100,000worldwide;theincidenceishigher(≈1:10,000)innorthernScandinavia.
in state c with the formation of permanent actin-myosin complexes (i.e., the rigor state). In this state, the muscle is rigid, and the condition is termed rigor mortis.
As already noted, formation of the thick filaments involves the association of myosin molecules in a tail-totail configuration to produce a bipolar orientation (see
Fig. 12.6 ). Such a bipolar orientation allows myosin to pull the actin filaments toward the center of the sarcomere during the cross-bridge cycle. The myosin molecules are also oriented in a helical array in the thick filament in such a way that cross-bridges extend toward each of the six thin filaments surrounding the thick filament (see
Fig.